Anti-cancer therapy utilizes a combination of therapeutic interventions such as surgery, radiation therapy and chemotherapy. Surgery and radiation therapy are generally confined locally to the main site of tumor growth, while chemotherapy is applied to prevent tumor re-growth or against distant tumor foci. Chemotherapeutic agents are also used to reduce tumor growth to manage disease progression when radiotherapy or surgery is not an option.
Immunosuppressive agents are clinically used to suppress a pathological immune reaction which targets the own body (autoimmunity) or overshooting immune reactions as seen in allergy. They are also used to treat transplant rejection caused by the immune system. Basic to immune responses is activation and proliferation of T cells following antigenic stimulation, which act in turn as helper cells for B cells, regulatory cells or effector cells. Immunosuppressive agents such as rapamycin or cyclosporine A act by inhibiting early T cell activation/proliferation. As both cancer and immune responses involve cell proliferation, some agents, for example rapamycin or its analogs, were initially used for immunosuppression but found later application as anticancer agents (Recher et al., Blood 2005, 105:2527-34).
Chemotherapeutic drugs are most effectively used in combination therapy. The rationale is to apply drugs that work via different mechanisms in order to decrease the probability of developing drug-resistant cancer cells. Combination therapy also allows, for certain drug combinations, an optimal combined dose to minimize side effects. This is crucial as standard chemotherapeutic agents target essential cellular process such as DNA replication, cell division or induce DNA damage and thus have a general cytotoxic effect. Finally, combination treatment of two compounds may uncover unanticipated synergisms and trigger effects not induced by a single compound. In recent years, drugs are also used in a neoadjuvant setting, i.e. prior to surgery, to reduce the tumor mass or to improve long-term survival.
Syrosingopine is a synthetic derivative of reserpine, an anti-hypertensive and anti-psychotic agent (J.A.M.A., Vol. 170, Nr. 17, Aug. 22, 1959, p. 2092). Syrosingopine was introduced clinically in the late 1950s. The reserpines are rarely used today due to the development of better drugs with fewer side-effects. Reserpine acts by inhibition of the vesicular monoamine transporter leading to catecholamine depletion and this mode of action is believed to be shared by all the reserpine derivatives with an anti-hypertensive effect. Although it has been clinically used, syrosingopine is relatively poorly studied compared to reserpine and has never been investigated as an anti-cancer agent.
Mitochondria contain the energy generating system of a cell, whereby electrons from metabolism pass through complexes I-IV of the electron transfer chain (ETC) leading to extrusion of protons from complex I, III and IV and to a reflux of protons through complex V with concomitant formation of chemical energy in the form of adenosine triphosphate (ATP). Oxygen serves as the ultimate electron acceptor and is reduced to H2O. Critical in this process is the inner mitochondrial membrane, as protons extruded from the complexes pass from the matrix through this membrane into the inter-membrane space, generating a positive membrane potential of 150-200 mV. Dyes such as TMRM (tetramethylrhodamine methyl ester) pass this membrane and accumulate in the mitochondrial matrix, whereby the intensity of the fluorescent signal depends on the strength of the membrane potential. A number of well described agents inhibit mitochondrial function and may be regarded as mitochondriotoxic agents. So called uncoupling agents such as FCCP (carbonyl cyanide-p-trifluoromethoxyphenyl-hydrazone) uncouple the flow of protons from ATP synthesis, leading to a collapse of the membrane potential with resulting loss of ATP synthesis. A number of well described mitochondrial inhibitors target the different complexes of the ETC including metformin, rotenone, epiberberine, piericidin A (all inhibitors of complex I), sodium malonate and thenoyltrifluoroacetone (inhibitors of complex II), antimycin A (complex III inhibitor), potassium cyanide and sodium azide (inhibitors of complex IV), and oligomycin (complex V inhibitor). Mitochondria are believed to be ancestrally engulfed bacteria. They contain a DNA genome encoding several components of the ETC, as well as components of the mitochondrial ribosome. Agents targeting the mitochondrial genome such as certain HIV-inhibitors of the class of nucleoside analogs, e.g. stavudine (D4T), are toxic for mitochondria as they ultimately destroy the ETC and the mitochondrial energy generating system.
Metformin is a widely used biguanide drug for type 2 diabetes. It is related to buformin and phenformin, two biguanides not used anymore in diabetes due to toxicity. Metformin is safe and well-tolerated and has been used in long-term management of diabetes for over 50 years and is the most-prescribed anti-diabetic drug worldwide. The main clinical benefit of metformin in the treatment of type 2 diabetes is the suppression of hepatic gluco-neogenesis to reduce hyperglycemia and improved insulin sensitivity; these effects are believed to be exerted by metformin-dependent stimulation of AMP-activated protein kinase (AMPK) activity. Basic to this effect is the fact, that metformin and other biguanides inhibit complex I of the respiratory chain (electron transfer chain) of mitochondria (EI-Mir et al., J Biol Chem 2000, 275:223-228) A meta-analysis of diabetic patients receiving metformin versus an unrelated anti-diabetic agent revealed that the metformin receiving cohort had lower incidence of cancer (Evans et al., BMJ 2005, 330:1304-5; Bowker et al., Diabetes Care 2006, 29:254-8). This has stimulated recent research into the use of metformin as an anti-cancer agent or prophylactic with numerous studies and trials in progress, see Gonzalez-Angulo et al., Clin Cancer Res 2010, 16:1695-700.